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The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-?
during Chlamydia trachomatis infection
#MMPMID25070851
Zhang Y
; Yeruva L
; Marinov A
; Prantner D
; Wyrick PB
; Lupashin V
; Nagarajan UM
J Immunol
2014[Sep]; 193
(5
): 2394-404
PMID25070851
show ga
IFN-? has been implicated as an effector of oviduct pathology resulting from
genital chlamydial infection in the mouse model. In this study, we investigated
the role of cytosolic DNA and engagement of DNA sensors in IFN-? expression
during chlamydial infection. We determined that three-prime repair exonuclease-1,
a host 3' to 5' exonuclease, reduced IFN-? expression significantly during
chlamydial infection using small interfering RNA and gene knockout fibroblasts,
implicating cytosolic DNA as a ligand for this response. The DNA sensor cyclic
GMP-AMP synthase (cGAS) has been shown to bind cytosolic DNA to generate cyclic
GMP-AMP, which binds to the signaling adaptor stimulator of IFN genes (STING) to
induce IFN-? expression. We determined that cGAS is required for IFN-? expression
during chlamydial infection in multiple cell types. Interestingly, although
infected cells deficient for STING or cGAS alone failed to induce IFN-?,
coculture of cells depleted for either STING or cGAS rescued IFN-? expression.
These data demonstrate that cyclic GMP-AMP produced in infected cGAS(+)STING(-)
cells can migrate into adjacent cells via gap junctions to function in trans in
cGAS(-)STING(+) cells. Furthermore, we observed cGAS localized in punctate
regions on the cytosolic side of the chlamydial inclusion membrane in association
with STING, indicating that chlamydial DNA is most likely recognized outside the
inclusion as infection progresses. These novel findings provide evidence that
cGAS-mediated DNA sensing directs IFN-? expression during Chlamydia trachomatis
infection and suggest that effectors from infected cells can directly upregulate
IFN-? expression in adjacent uninfected cells during in vivo infection,
contributing to pathogenesis.
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